ProMIS has developed a rigorous screening and validation process to select the best products to develop among our emerging portfolio of precision therapeutics for Alzheimer’s and ALS. As shown in the figure below, the process starts with identifying specific targets (epitopes) on the prion forms of misfolded proteins, known to play a causative role in the development and progression of AD and ALS. ProMIS uses its proprietary technologies, ProMISTM and Collective Coordinates, to identify these targets. Specific murine monoclonal antibodies (mabs) are raised against these targets and evaluated in a 3-step process, to identify the best products to take into clinical development.
Initial Screening for Binding. This phase allows to identify mabs that bind uniquely and specifically to the prion strains of the misfolded proteins driving AD (Amyloid beta and Tau proteins) and ALS (SOD1 and TDP43 proteins). The top candidate products, showing selective binding to the prion forms and no binding to the non toxic forms, are selected for the validation phase in human tissue.
Validation in human tissue. The several product candidates chosen after successful screening are now evaluated to confirm their unique and specific binding profiles in cadaveric tissue (brain samples) and cerebrospinal fluid (CSF) from patients with a confirmed diagnosis of AD. For example, in the case of AD product candidates, our validation program is designed to identify those mabs that show binding to the prion forms of Amyloid beta in the cadaveric tissue, with no off target binding to inert Aβ monomers or plaque. Validated mab products that show this target product profile in human tissue undergo a final assessment in functional assays to select the ideal products for clinical development.
Functional Assays & final product selection. Two complementary assays are used to identify, among the validated product candidates, those that demonstrate blocking of neurotoxicity (blocking the killing of neurons, a hallmark of disease) and inhibition of propagation of the prion-like strains of misfolded protein (also a hallmark of disease). Validated products meeting these criteria will be chosen for clinical development.
Alzheimer’s Products. ProMIS has identified multiple product candidates against five unique targets on misfolded strains of Aβ that have successfully passed the screening phase. Among these, Five lead antibodies, along with several backup candidates, have been confirmed with the ideal target binding profile in brain tissue and CSF from AD patients.. In addition, ProMIS is currently raising mab product candidates against a sixth unique misfolded Aβ target. Finally, ProMIS is in the process of initiating identification of unique targets on toxic strains of Tau protein.
ALS Products. ProMIS ALS portfolio consists of three anti-SOD1 mab products that are fully validated and confirmed in multiple functional assays, showing blocking of both the neurotoxicity and the propagation of prion-like strains of misfolded SOD1. In addition, ProMIS is initiating the process to identify unique targets on toxic, misfolded strains of TDP43.
Harnessing the power of precision medicine to conquer Alzheimer’s disease.